Project Summary Lumbar spinal stenosis (LSS) disproportionately affects older adults and is the most common reason for lumbar spine surgery. The biological mechanism underlying degeneration in lumbar spinal stenosis has not been fully elucidated. Emerging data suggest that TTR amyloidosis, characterized by deposition of the misfolded protein transthyretin (TTR), is age-dependent, unrecognized, and commonly present in the surgical specimens (e.g. ligamentum flavum) in LSS that may precede the development of cardiac involvement by several years. However, the proportion of LSS caused by TTR amyloidosis is not well defined nor it is clear if cardiac involvement is present at the time of amyloid deposits in the lumbar spine. Uncovering an association between lumbar spinal stenosis and TTR amyloidosis may provide a modifiable biological mechanism for acquired degenerative lumbar spinal stenosis and could lead the path toward further clinical trials of novel compounds prevent amyloid formation. Additionally, since TTR amyloidosis results in a cardiomyopathy, leveraging a highly specific non-invasive imaging test (Tc-99 pyrophosphate scintigraphy or PYP), that can identify TTR cardiac amyloidosis without the need for histology; we may be able to identify a group of patients with TTR cardiac amyloid before the development of overt heart failure. Identification of TTR cardiac amyloidosis early in their disease course is critical as multiple emerging therapies prevent new amyloid deposition but do not address existing amyloid. Accordingly, we now propose a prospective pilot cohort study in patients age >65 years old who are undergoing LSS surgery in which we will screen surgical specimens for transthyretin amyloidosis (ATTR) using pathologic techniques including tissue typing with mass spectrometry based proteomic analysis. In patients with pathologically defined ATTR disease, we will characterize their cardiac phenotype using biomarkers, transthoracic echocardiography and technetium pyrophosphate cardiac imaging and establish biochemical associations between disease phenotype and TTR instability. The aims of these studies are: (1) to confirm the previously reported high prevalence of TTR amyloid deposits among elderly patients undergoing lumbar spinal stenosis surgery, and (2) to characterize the cardiac phenotype and establish biochemical associations of TTR stability in patients with pathologically defined TTR amyloidosis. This multidisciplinary study could result in more routine evaluation for TTR amyloid in lumbar spine specimens, patients with ATTR cardiac amyloid being diagnosed at an earlier disease state and future disease-modifying interventions in older adult patients undergoing lumbar spinal stenosis surgery. Collectively, such studies will facilitate a precision medicine approach to improve outcomes in older adults with LSS and TTR amyloid cardiomyopathy.